Compositions for protection against superficial vasodilator flush syndrome, and methods of use

ABSTRACT

Compositions for protection against SVFS syndromes are composed of a flavonoid compound of the basic structures 2-phenyl-4H-1-benzopyran or 2-phenyl-4-keto-1-benzopyran or glycosides thereof, an inventive olive kernel extract and a non-bovine sulfated proteoglycan, and, optionally, one or more of bitter willow extract, D-glucosamine sulfate and serotonin inhibitor.

This application is a CIP of co-pending U.S. Ser. No. 10/811,823, filedMar. 30, 2004, which was a CIP/Div of co-pending PCT/US02/00476, filedJan. 3, 2002, which was a continuation of co-pending U.S. Ser. No.09/771,669, filed Jan. 30, 2001 (now U.S. Pat. No. 6,984,667), which wasa CIP/Div of co-pending U.S. Ser. No. 09/056,707, filed Apr. 8, 1998(now U.S. Pat. No. 6,689,746.

BACKGROUND OF THE INVENTION

The invention is generally related to the treatment of inflammatoryconditions. More specifically, the invention is related to compositionscontaining inhibitors of mast cell activation and secretion such as aproteoglycan that are designed to be used as dietary supplements oradjuvants to conventional approved medications for protection againstsuperficial vasodilator flush syndrome (“SVFS”).

There have been a number of mostly anecdotal reports that theproteoglycan chondroitin sulfate, as well as glucosamine sulfate, aproduct of the intestinal breakdown of proteoglycans, may be helpful inrelieving the pain of osteoarthritis:—Shute N. Aching for an arthritiscure. US News and World Report, Feb. 10, 1997.—Cowley G. The arthritiscure? Newsweek, Feb. 17, 1997; Foreman J., People, and their pets, toutarthritis remedy. The Boston Globe, Apr. 7, 1997; Tye L. Treatment gainsscientific attention. The Boston Globe, Sep. 25, 2000.

A recent meta-analysis showed potential therapeutic benefit ofchondroitin sulfate and/or glucosamine in osteoarthritis [McAlindon etal. J Am Med Assn. 283:1469 (2000)], while a double-blind clinical trialwith glucosamine showed definite benefits in osteoarthritis with respectto both pain and radiographic joint appearance [Reginster et al., Lancet337:252 (2001)]. However, less than 5% of the chondroitin sulfate incommercially available preparations is absorbed orally, because the sizeof the molecule and the degree of sulfation impede its absorption fromthe gastrointestinal tract. Furthermore, such commercial preparationsuse chondroitin sulfate obtained from cow trachea, with the possibledanger of contracting spongiform encephalopathy or “mad cow disease”. Infact, the European Union has banned even cosmetics that containbovine-derived products.

Theoharides et al. British Journal of Pharmacology 131:1039 (2000)indicated for the first time how proteoglycans such as chondroitinsulfate may work. The paper reported that chondroitin sulfate and, to alesser degree, glucosamine sulfate, inhibit activation of mast cellsthat are known to trigger allergy and asthma. This discovery is thebasis for Theoharides, U.S. patent application Ser. No. 09/056,707,filed Apr. 8, 1998 and 09/773,576, filed Feb. 2, 2001.

Mast cells are also now recognized as important causative intermediaryin many painful inflammatory conditions[Galli, N Eng J. Med. 328:257(1993); Theoharides, Int J Tissue Reactions 18:1 (1996)], such asinsterstitial cystitis and irritable bowel syndrome [Theoharides, Ann NYAcad, Sci. 840:619 (1998)], as well as in migraines and possiblymultiple sclerosis [Theoharides, Persp Biol Med. 26:672 (1983);Theoharides, Life Sci 46:607 (1996)]. In fact, glucosamine was recentlyconsidered to be prophylactic for migraines [Russell, Med Hypoth 55:195(2000)].

Mast cells are increasingly implicated in conditions involving inflamedjoints, such as in osteoarthritis and rheumatoid arthritis, throughactivation of local mast cells by, for example, neuropeptides, such asSubstance P. Additional indirect evidence also supports the involvementof mast cells in bone resorption: (a) systemic mastocytosis isinvariably associated with osteoporosis; (b) inhibition of mast cellmediator release reversed lytic bone changes; (c) depletion of mastcells inhibited bone resorption in organ culture; (d) human synovialmast cells were shown to secrete in response to allergic andnon-immunologic stimuli; (e) human mast cells release the cytokine IL-6and (f) IL-6 has been definitively linked to bone resorption andosteoporosis.

It was recently shown that chondroitin sulfate's ability to inhibit theactivation of mast cells compliments the inhibitory effects on mast cellactivation of another class of naturally occurring compounds, theflavonoids [Middleton et al. Pharm Rev 52:1 (2000)]. Certain plantflavones (in citrus fruit pulp, seeds, sea weed) are now recognized asanti-allergic, anti-inflammatory, anti-oxidant and cytoprotective withpossible anti-cancer properties. Only some flavonoids that belong to thesubclass of flavones, e.g., quercetin, inhibit mast cell activation.

Quercetin inhibits secretion from human activated mast cells [Kimata etal. Allergy 30:501(2000)], and has also been used effectively for thetreatment of chronic prostatitis [Shoskes et al., Urology 54:960(1999)]. However, other flavonoids may have opposite effects. Use of theterm “bioflavonoids” or “citrus flavonoids” in certain commercialproducts, therefore, provides little information, and may includemolecules that have detrimental effects; for example, soy containsisoflavones that have estrogen-like activity that worsens inflammatoryconditions.

Theoharides, U.S. Pat. No. 6,689,748 and co-pending U.S. patentapplication Ser. No. 10/439,301, the contents of which are incorporatedby reference, claim the oral use of proteoglycans, without and withflavonoids, for the treatment of mast cell activation-induced diseases.Absorption of these compositions from the gastrointestinal tract andsynergism with other treatment modalities were not addressed in theseapplications.

Theoharides has described the use of antagonists of the action ofCorticotropin Releasing Hormone (also known as Corticotropin ReleasingFactor) in inhibiting myocardial mast cell activation in myocardialischemia (copending U.S. patent application Ser. No. 08/858,136, filedMay 18, 1997), in treating stress-induced skin disease (U.S. Pat. No.6,020,305) and stress-induced migraine headaches (U.S. Pat. No.5,855,884), the contents of which are incorporated herein by reference.The synergistic effects of the compositions of the present inventionthat include antagonists of the actions of Corticotropin ReleasingHormone (“CRH”) on mast cells were not recognized at the time of theprevious studies. The word “antagonists” in connection with CRH isintended herein to include any molecule that prevents the actions of CRHon target cells, and includes, but is not limited to, anti-CRHneutralizing antibodies or binding proteins, or molecules preventing therelease of CRH at local sites (see below for details). The term“syndrome”, as used herein, is intended to mean an aggregate of signsand symptoms that together constitute a disease

Theoharides has also described a method for treating patients with mastcell derived molecules-induced interstitial cystitis with histamine-1receptor antagonists (U.S. Pat. No. 5,994,357). Treatment of mast cellmolecules-induced migraines with histamine-1 receptor antagonists is thesubject of Theoharides U.S. Pat. No. 5,855,884. Histamine-3 receptoragonists as pharmaceutical agents in mast cell-involved diseases aredescribed in Theoharides U.S. Pat. No. 5,831,259. The contents of thesethree patents are incorporated herein by reference. At the time of thisinvention the synergistic effects of the present compositions with suchantagonists had not yet been recognized.

Another type of inflammatory condition is referred to generically assuperficial vasodilator flush syndrome (“SVFS”). This syndrome ispresent in a group of human inflammatory conditions that includescarcinoid-induced flush, niacin-induced flush, mesenteric fractionsyndrome induced flush, serotonin induced flush, postmenopause inducedflush, alcohol-induced flush and monosodium glutamate (“MSG”) inducedflush.

The most potent agent for reversing the trend to increased serum levelsof cholesterol and triglycerides and increased levels of serum HDL isniacin. Unfortunately, compliance with the niacin treatment regimen isofter compromised by the development of a feeling of warmth and itching,especially in the face (flush), even with the use of slow or extendedrelease niacin preparations.

An important need therefore exists for compositions for administrationto human patients being treated for mast cell-induced inflammatorydiseases by various modalities, that are synergistic in that they havestronger effects than the sum of the effects of the individualcomponents, and also synergistic with conventional clinical treatmentsof inflammatory conditions. “Synergistic” is also intended to mean:“coordinated or correlated action by two or more structures or drugs”[Stedman's Medical Dictionary, 23rd edition, Williams & Wilkins]. Animportant need exists for a solution to the niacin flush problem inpatients, particularly with those suffering with coronary arterydisease. An important need also exists for formulations that increasethe absorption from the gastrointestinal tract, nasal passages and skinsurface of the compositions of the invention. Such formulations havebeen discovered, and are described below.

SUMMARY OF THE INVENTION

The invention comprises compositions for human use containing aflavonoid compound having the basic structure of2-phenyl-4H-1-benzopyran or its 4-keto counterpart, a heavily sulfatedproteoglycan, olive kernel extract (“OKE”), sulfated glucosamine, and,optionally, and one or more active ingredients selected from the groupconsisting of a serotonin antagonist, bitter willow extract,S-adenosylmethionine (“SAM”), histamine-1 receptor antagonists,histamine-3 receptor agonists, antagonists of the actions of CRH,caffeine, folic acid, polyunsaturated fatty acids, and polyamines,together with appropriate excipients and carriers, said compositionshaving improved absorption from the gastrointestinal tract, skinsurface, and nasal and pulmonary surfaces, and anti-inflammatory effectssynergistic with each other and synergistic with available conventionalclinical treatment modalities.

In preferred embodiments, the sulfated glucosamine is D-glucosaminesulfate, the proteoglycan is chondroitin sulfate, and the flavonoidcompound is, preferably, quercetin, luteolin, genistein, myricetinand/or their respective glycosides.

In still other embodiments serotonin inhibitors used in anti-flushformulations include prochlorperazine, cyproheptadine and azatadine.

In yet another embodiment, inventive compositions that protect humansagainst a variety of superficial vasodilator flush syndromes include aflavonoid compound, an inventive olive kernel extract, a non-bovinechondroitin sulfate and, optionally, one or more of D-glucosaminesulfate, bitter willow ectract, and a serotonin inhibitor

In another embodiment, compositions may also contain antagonists of theeffects of CRH on mast cells or other target cells of the myocardium,gastric mucosa, urinary bladder, skin, meningeal membranes, andblood-brain barrier.

In still another embodiment, the inventive compositions may be used ascoatings on medical devices, not only to protect surrounding tissuesfrom inflammation due to the devices, but also to treat innateinflammation in surrounding tissues.

In another embodiment, the inventive compositions are used against theinflammatory processes of endometriosis.

In yet another embodiment, the inventive compositions are used againstthe inflammatory components of hormonally-related cancers, such asbreast, testicular, ovarian and uterine cancers, and when supplementedwith chemotherapeutic agents are used against the cancer itself.

In still another embodiment, the inventive compositions may be used inthe treatment of multiple sclerosis.

In another embodiment, the inventive olive kernel extract is used toimprove the absorption of drugs across membrane barriers in the body,such as those of the intestine, skin and pulmonary alveoli.

In yet another embodiment, the inventive compositions may be used in thetreatment of fibromyalgia.

The inventive olive kernel extract may be used to increase theabsorption of difficulty-absorbable drugs across the intestine, skin andpulmonary alveoli.

FIGURES

FIG. 1 shows the basic structure of a flavone compounds,2-phenyl-4H-1-benzopyran and its 4-keto counterpart, that are active incarrying out the invention. The active flavonoids differ mostly only inthe presence or absence of hydroxyl groups at ring positions 5, 7, 2′,3′, 4′ and 5′.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

It has been discovered that a combination of a flavonoid compound or itsglycoside counterpart, a sulfated proteoglycan, a olive kernel extract“)KE”), a sulfated D-hexoseamine, and, optionally, one or more of aserotonin antagonist, bitter willow extract, a CRH antagonist, ahistamine-1 receptor antagonist, a histamine-3 receptor agonist,polyamines, rutin and caffeine has synergistic anti-inflammatory effectswhen used as a dietary supplement, a topical product or an aerosol fornasal or pulmonary administration, without or with a conventionalclinical treatment for inflammatory diseases. Within the presentcontext, such inflammatory diseases result from the activation,degranulation and consequent secretion of inflammatory biochemicals frommast cells, and the resultant inflammatory diseases include the groupconsisting of: allergic inflammation, arthritis (to includeosteoarthritis and rheumatoid arthritis), fibromyalgia, inflammatorybowel disease, interstitial cystitis, irritable bowel syndrome,migraines, atherosclerosis, coronary inflammation, ischemia, chronicprostatitis, eczema, multiple sclerosis, psoriasis, sun burn,periodontal disease of the gums, superficial vasodilator flushsyndromes, hormonally-dependent cancers, endometriosis and medicaldevices. The OKE kernel extract alone may be used to improve thetransmembrane transport of difficulty-absorbable drugs in the intestine,skin and pulmonary alveoli.

In a highly preferred embodiment, the sulfated proteoglycan isnon-bovine chondroitin sulfate, preferably from shark cartilage, whichblocks mast cell activation, degranulation and consequent secretion ofinflammatory biochemicals from the mast cells. Other natural sulfatedproteoglycans suitable for practicing this invention include keratansulfate, dermatan sulfate and hyaluronic acid sodium salt (sodiumhyaluronate). The preferred biological source of the chondroitin sulfateis shark cartilage which is more-highly sulfated than the commoncommercial chondroitin sulfate isolated from cow trachea; the sharkcartilage source also avoids the potential dangers associated withbovine sources.

The highly preferred flavone is quercetin which inhibits secretion ofinflammatory molecules from mast cells by affecting moesin, a unique 78kDa mast cell protein [Theoharides et al. J Pharm Exp Therap 294:810(2000)]. In addition to quercetin, other flavones suitable in carryingout the invention include the quercetin glycoside rutin, myricetin,genistein, kaempferol, the isoflavone phenoxodiol, and the kaempferolglycoside astrazaline.

The OKE component of the inventive compositions is preferably anunrefined (first pressing, filtered, oleic acid-related acidity <3%,water content <1%) extract product produced, for one source, on theisland of Crete in Greece. This kernel extract product is especiallyprepared by applicant's process consisting essentially of: (1)harvesting first collection ripe olives, preferably in December; (2)compressing the oil from the flesh of the ripe olives; (3) washing thekernels remaining after step (2) with water to remove debris; (4) dryingthe washed kernels with a stream of hot air; (5) crushing the driedkernels to produce an extract; (6) extracting the extract from step (5)with an organic solvent (e.g., hexane, heptane, octane) plus steam; (7)removing particulate matter from the organic extract by centrifugationor microfiltering through 1-2 micron pore size filters; (8) evaporatingthe organic solvent and water from the clarified extract of step (7) bymaintaining the extract at 86-100° C. while percolating helium (to avoidoxidation) through the fluid, which process reduces the water content to<1%, the acidity (as oleic acid) to <3%; and, the organic solvent to<1%; and (8) storing the final kernel extract product in the absence ofair.

The inventive OKE surprisingly has the unique property of increasingabsorption of the other components of the anti-inflammatory compositionsthrough the intestinal mucosa or skin, and also adds its own content ofimportant anti-oxidants, such as omega fatty acids (e.g.,eicosapentanoic acid) and alpha tocopherol. The polyphenols found insuch olive kernel extracts also have anti-inflammatory effects in, forexample, arthritis [Martinez-Dominguez et al., Inflamm. Res. 50:102(2001)]. E.B.E.K., Inc., Commercial, Industrial Enterprises of Crete,118 Ethnikis Antistasecos, Heraklion, Crete, 71306, Greece, will preparethe extract product according to applicant's above-described procedurefor commercial users.

In addition to its usefulness in increasing the absorption of theinventive compositions across the intestinal wall and the skin, theinventive OKE product is useful in aiding the dissolution of other drugsprior to administration to a patient, and is useful in promoting theabsorption of other difficulty-absorbable drugs, e.g., theHDL-increasing drug torcetrapib (DeNinno et al. U.S. Pat. No.6,586,448), across intestinal mucosa, oral mucosl, nasal mucosa, andskin of patients.

Inhibitors of mast cell activation and consequent secretion ofinflammatory molecules may be used in the treatment of inflammatoryprocesses such as in SVFS, that includes niacin, carcinoid, menopausal,mesenteric fraction, serotonin, alcohol and MSG induced flush syndromes(see Example 12, below). Applicant has discovered that certain flavonoidcompounds of the basic structures 2-phenyl-4H-1-benzoyran and its 4-ketocounterpart (described in the legend and figure of FIG. 1.),particularly, quercetin, luteolin, rutin, myricetin, genistein, inhibitflush syndromes in humans (Example 19) and in rat models (Example 20).

In experiments with rat models of the flush syndrome, applicant hassurprisingly discovered that serotonin mediates the flush syndromeinduced by niacin administration. This discovery has opened up a newtherapeutic approach for niacin flush. Applicant has discovered thatserotonin inhibitors/antagonists such as prochlorperazine,cyproheptadine, azatadine and ketanserin when used alone or incombination with the basic composition of the invention inhibit theniacin flush syndrome (Example 20, below).

Optional supplementation of the compositions described above with themethylation reagent S-adenosylmethionine (“SAM”) adds antioxidant,anti-inflammatory and cytoprotective properties, particularly ininflammatory joint diseases. Addition of SAM also accelerates metabolismof homocysteine, which amino acid has been implicated in coronarydisease, to cysteine, which is harmless. Folic acid may be added tocertain of the present formulations for similar reasons.

Another optional supplement to the basic compositions of the inventionis a histamine-1 receptor antagonist, such as hydroxyzine, merelastine,azelastine, azatadine and cyproheptadine. Other histamine-1 receptorantagonists are described in Table 25-1 in Goodman and Gilman's ThePharmaceutical Basis of Therapeutics, 9^(th) ed., New York, 1996.Histamine-3 receptor agonists are described in the Theoharides patentslisted above.

Hormone-dependent cancers, including the estrogen/progestin linkedovarian, uterine, breast, and endometrial cancers, and theandrogen-linked testicular cancers, are associated with tissueinflammation. These inflammations can be treated with chondroitinsulfate, quercetin, genestein, phenoxodiol isoflavone, OKE, and,optionally, chemotherapeutic agents such as tomoxifen or raloxifen.

Pelvic inflammatory conditions, such as presents in endometriosis, canalso be treated with the inventive compositions. Particularly useful inthis regard are compositions delivering chondroitin sulfate, quercetinor luteolin, and hydroxyzine.

The inventive compositions may also be used as coatings on implantedmedical devices, which devices may lead to or be associated withinflammation of surrounding tissues, in order to provide protectionagainst such inflammations. Not only can the coating of such medicaldevices inhibit or protect against inflammation caused by the deviceitself, but the coated devices can also be used to deliver the inventivecompositions to innately inflamed tissues due to other causes. Suchmedical devices include artificial skins (scaffolding such as naturallyoccurring polymers, e.g., collagen; man-made polymers, e.g., PTFE,Dacron, PET or polyethylene; self-degrading man-made polymers, e.g., PLAor PGA; biopolymer matrices from animal tissues including fetal andneonatal tissues to be used as tissue engineering scaffolds (cf. Bell etal., U.S. patent application Pub. No. 20020146393)), artificial joints,band-aids, stents for blood vessels, artificial blood vessels,pacemakers, stents for abdominal support in hernia repair, tissuetransplants, prostheses, breast implants, etc. Particularly useful inthis regard are compositions containing heavily sulfated, non-bovineproteoglycans (e.g., chondroitin sulfate) and flavonoids (e.g.,quercetin, myricetin, gentistein).

Sources of CRH antagonists include, in addition to the Theoharidespatents listed in the Background section above: Neurocrine Biochem.Inc.'s D-Phe 12 Nle Ala32,21,38hCRH(12-41)NH2, cat no. 1P-36-41; Pfizernon-peptide CP-154,526-1; Sigma Chem., St. Louis anti-CRH polyclonalantiserum; and Pfizer, N.Y. patents and applications: U.S. Pat. No.6,211,195, U.S. Pat. No. 5,795,905, PCT/IB95/00573, PCT/IB95/00439, U.S.Ser. No. 08/448,539, U.S. Ser. No. 08/481,413, U.S. Ser. No. 09/735,841,and in Owens et al. Pharm. Rev. 43:425 (1991).

The preferred concentration range of the proteoglycan, hexosaminesulfate and flavone components of the oral formulations are 10-3,000 mgper tablet or capsule. The preferred concentration range for SAM is3-1,000 mg per capsule or tablet. Generally, where present, the amountsof the unrefined kernel extract are at least three times those of theother active ingredients, preferably 300-1200 mg. The number of capsulesor tablets to be taken per day is determined by the nature and severityof the medical condition, and is readily determinable by the patient'shealth provider. Other representative formulations are described in theexamples below.

The compositions of the invention may be formulated in any standardmeans of introducing pharmaceuticals into a patient, e.g., by means oftablets or capsules. The compositions of the invention include ointmentsand creams for skin conditions, mouth washes and toothpaste forperiodontal diseases, and solutions for nasal aerosols. Standardexcipients and carriers for the active ingredients of the inventivecompositions are described in Remington's Pharmaceutical Sciences, MackPublishing Co., Easton, Pa.

Although not bound by any particular mechanism of action of thecomponents of the claimed compositions, the inventor contemplates thatthe proteoglycan inhibits the activation and degranulation of therelevant mast cells, while the flavone inhibits the secretion ofinflammatory biomolecules from these mast cells. “Activation” and“degranulation” of mast cells are defined herein as is standard and wellknown in this art, that is, to mean synthesis and secretion from theactivated mast cell of any type of molecule(s) that alone or incombination triggers inflammatory processes.

EXAMPLES Example 1

Table 1 compares chondroitin sulfate-containing commercial products tothe present compositions. TABLE 1 Comparison of ChondroitinSulfate-Containing Products to Present Invention Product Most AvailablePresent Invention Compositions Main ingredient Mixture of chondroitinsNon-bovine chondroitin sulfate, preferably the C type Source Cow tracheaShark cartilage Amount per capsule or 100-300 10-3000 mg tablet Degreeof sulfation Low, if any High Absorption from g.i. tract <5% >15% TargetUnknown Mast cells, inflammatory cells Other ingredients Vitamins, fishoils Flavones, unrefined (some preparations) kernel olive oil, SAM,histamine-1 receptor antagonists, histamine-3 receptor agonists, CRHantagonists, polyamines, caffeine, folic acid Advantages None knownAnti-allergic, anti- inflammatory, anti- oxidant, cytoprotective Adverseeffects Risk of mad cow None known disease, spongiform encephalopathy,stomach upset, allergy to fish products Relevant conditionsOsteoarthritis Flush syndromes, inflammatory angina, asthma coronaryartery disease, arthritis (osteoarthritis or rheumatoid arthritis),chronic prostatitis, eczema, fibromyalgia, interstitial cystitis,irritable bowel syndrome, inflammatory bowel disease, migraines,multiple sclerosis, psoriasis, periodontal disease, cancer (includinghormonally- dependent forms). Scientific publications None foundTheoharides et al. Br J Pharm 131:1039 (2000) Middleton et al. Pharm Rev52:673 (2000)

In all examples, chondroitin sulfate is to assumed to be of a non-bovinevariety.

Example 2

Composition For Protecting Against Inflammatory Diseases Ingredients.per capsule. mg: *Chondroitin sulfate 150-300 *D-Glucosamine sulfate150-300 *Quercetin or luteolin 150-300 *Olive kernel extract 350-1200Two capsules to be taken orally 2-3 times daily, at least one hourbefore meals

Example 3

Composition For Protecting Against Arthritis Ingredients per capsule,mg: *D-Glucosamine sulfate 150-300 *Chondroitin sulfate 150-300 *Sodiumhyaluronate 100-200 *Quercetin or luteolin 150-300 *Olive kernel extract350-1200

Example 4

Topical Composition For Protecting Against Arthritis Ingredients % byweight *D-glucosamine sulfate 5 *Condroitin sulfate 5 *Sodiumhyaluronate 0.5 *Bitter willow bark extract 5 *Quercetin or luteolin 3*Aloe vera 10 *Olive kernel extract 5Skin ointment or cream. Apply three times per day to affected areas.

Example 5

Composition For Protecting Against Cardiovascular Disease mg/capsule:*Kaempferol or luteolin 100-300 Rutin 100-500 *S-adenosylmethionine 50-400 *Niacin 100-1,000 Folic acid  10-150 *Olive kernel extract350-1200 *Bitter willow bark extract 5% by weight *Polyunsaturated fattyacids (DHA,DPA) 100-600

Example 6

Composition For Protecting Against Periodontal Disease Mouthwash:*Chondroitin sulfate 0.04-0.4 M *Quercetin or luteolin 0.04-0.4 M*In a standard mouthwash vehicle

Example 7

Toothpaste Composition Toothpaste, mg %: *Chondroitin sulfate 5-500*Quercetin or luteolin 3-300 *D-glucosamine sulfate 5-500 *Olive kernelextract 1-100*In a standard toothpaste vehicle

Example 8

Sunscreen composition Ingredients mg % *Chondroitin sulfate 5-50*D-glucosamine sulfate 5-50 *Quercetin 3-30 *Aloe vera 1-10 *Olivekernel extract 5 *Sun screen (e.g., TiO₂) 5

Example 9

Composition For Protecting Against Migraine Headaches Ingredients.mg/capsule: *Chondroitin sulfate  50-300 *Quercetin or luteolin 100-300*Azatadine  1-4 *Optionally, a CRH-receptor antagonist  5-300

Example 10

Oral Composition For Protecting Against Inflammatory Processes inRelapsing Multiple Sclerosis Ingredients, mg/capsule *Chondroitinsulfate  50-300 *Quercetin or myricetin  50-300 *Hydroxyzine  50-300*Optionally, olive kernel extract 350-1200 *Optionally, interferon-beta8 million IU Betaferon (Schering), s.c., on alternate days or 30 pg(Avonex, Biogen) i.m. once weekly, or Rebif (Serono) 44 ug s.c.*Optionally, a CRH receptor antagonist  5-300

Example 11

Composition For Protecting Against Cystitis And Prostatitis Ingredients,mg/capsule or tablet: *D-glucosamine sulfate 50 *Chondroitin sulfate100-300 *Sodium hyaluronate 200 *Quercetin 100-400 *Olive kernel extract350-1200

Example 12

Composition For Protecting Against “Flush” Ingredients, per capsule:*Chondroitin sulfate    50 mg *Quercetin 150-350 mg *Optionally, olivekernel extract 100-750 mg *Bitter willow bark extract 5% by weight*Optionally, cyproheptadine or    4 mg azatadine

Example 13

Cream Composition For Protecting Against Skin Allergy Ingredients: % byweight *Aloe vera 5 *Non-bovine chondroitin sulfate 5 *Myricetin 5*Alpha-tocopherol 5 *Olive kernel extract 5 *Aloe vera 10 *Optionally,azelastine or hydroxyzine 5

Example 14

Composition For Protecting Against Allergies and Allergic AsthmaIngredients, mg/tablet *Myricetin 500 *Chondroitin sulfate 200*Optionally, azelastine 4 *Rutin 500 *Optionally hydroxyzine 25

Example 15

Composition For Protecting Against Hormonally-Dependent CancersIngredients, mg/day Chondroitin sulfate  50-300 Quercetin  25-250Genestein  50-300 Phenoxodiol isoflavone 500-1000 Olive kernel extract350-1200 Optionally, tomoxifen or raloxifen About 10

Example 16

Composition For Protecting Against Allergic Conjunctivitis Ingredients:*Quercetin 0.05% *Chondroitin sulfate  2.0% *Optionally azelastine 0.05%

Example 17

Effect of Olive Kernel Extract on Absorption of a Proteoglycan SulfateIn Vivo

Chondroitin sulfate was tritiated by New England Nuclear Corp. to aspecific activity of 4.3 mCi/ml.

Unlabeled chondroitin sulfate was dissolved in olive kernel extract at aratio of about 55 w/v chondroitin sulfate powder to about 450 w/v ofolive kernel extract (2.9% acidity as oleic acid, 1.03% water, 0.08%hexane). To this solution was added 20.2 microcuries of the labeledchondroitin sulfate. AAA gelatin capsules were filled with the resultingsolution using an aluminum template molding device.

The laboratory animals (250 g male Sprague-Dawley rats) were keptovernight without food but with free access to water. One capsulecontaining the above-described chondroitin sulfate-olive kernel extractsolution was given to each rat per os. Control animals were given theequivalent amount of chondroitin, but without olive kernel extract. Theanimals were then given free access to food. Serum radioactivity wasmeasured 8 hours thereafter in a beta scintillation counter.

The results showed that, in control animals, about 3.9%+/−0.4% (n=3) ofthe dose of labeled chondroitin sulfate reached the circulation. Insharp contrast, in animals given the olive kernel extract along with thelabeled chondroitin sulfate, about 14.3%+/−0.7% (n=4) of the dose wasabsorbed into the general circulation.

These results demonstrate that olive kernel extract increased by almost400% the absorption of a proteoglycan from the intestine into thegeneral circulation.

Parallel experiments with codfish oil, corn oil and olive oil (from theflesh of the olive) were comtemplated, but chondroitin sulfatesolubility in these oils was insufficient to meet the requirements ofthe experiment.

Example 18

Composition for Protecting Against Endometriosis Composition mg/tabletRutin 500 Luteolin 500 Chondroitin Sulfate 500

Example 18 Method of Treating Niacin-Flush in Humans

Four normal male subjects (±years) were entered in the followingprotocol: On days 1 and 2, they were administered 1 gm immediate releaseniacin, at 2 pm. On days 3 and 4 they were administered 2 capsules ofthe composition of Example 12 that contained 150 mg quercetin and 450 mgof olive kernel oil per capsule. On days 4 and 6, they were administeredtwo Algonot capsules at 8 am and 1 g niacin at 2 pm. Skin temperaturewas measured with an infrared digital pyrometer at 4 facial sites(forehead, both checks and chin) at 15, 30, 45, 60, 75 and 90 min postniacin administration, along with daily room temperature subjects alsocompleted a symptoms questionnaire (erythema, edema, pruritus andburning sensation) on a scale of 0=no symptom and 5=maximal. There wasno significant increase in temperature rise with niacin administration,but symptoms ranged 4-5 and lasted 3-4 hrs. After administration of theinventive composition, the scores were reduced to 2-3 and lasted onlyabout 75 min. These results demonstrate that the inventive compositionscontaining a flavonoid will reduce niacin flush. / Niacin + Inventive /Niacin alone Composition Erythema 4.75 ± 0.5  4.5 ± 0.58 3.25 ± 0.5  2.5± 0.58 Edema  0.5 ± 0.58  0.5 ± 0.58 0.25 ± 0.5 0.25 ± 0.5 Urticaria2.25 ± 0.5  2.0 ± 0.82 1.75 ± 0.5 1.25 ± 0.5 Burning 4.75 ± 0.5  4.0 ±0.82  3.0 ± 0.82  2.5 ± 0.58 Duration (hr) 3.63 ± 1.11 2.75 ± 0.87 1.68± 0.40 1.68 ± 0.70

Example 20 Protection Against Niacin Flush in an Animal Model

A. Niacin Alone:

Niacin was administered to unanesthetized rats, using 3 animals perdose. Dose, mg Human equiv., mg .1 583 11.0 1,167 .1 1,750 12.0 2,334

Ear temperatures were determined 45 mins. after niacin administration.Baseline temperatures for rats is 26.5-28.5 degrees C. Ear temperaturesrose with all doses of niacin to a peak of +2 degrees C.

A. Treatment with Azatadine (histamine-1 receptor antagonist).

Rats were treated with 17.1 ug of azatadine i.p. at time zero. Niacin, 5mg, was given i.p. 30-480 mins. post-azatadine, and ear temperatureswere measured.

At 10 mins. azatadine had reduced the niacin +2 degrees C. by 75%.

B. Treatment with cyproheptadine (strong anti-serotonin antagonist)

Rats were treated with 8.55 ug of the antagonist i.p. at time zero, andniacin, 5 mg, was given at 120-480 mins. thereafter. Ear temperatureswere measured at 45 mins.

There was no effect of niacin in animals pre-treated withcyproheptadine.

C. Treatment with ketotifen (anti-H3)

Rats were pretreated with 17.1 ug of ketotifen, and niacin, 5 mg, wasadministered i.p. 30 mins. thereafter. Ear temperatures were measured 45mins. thereafter.

The drug had no significant effect on the niacin effect.

D. Treatment with Quercetin.

Quercetin, 4.7 mg, was given to rats i.p. at time zero, and 5 ng niacinadministered i.p. 120, 240 and 360 mins. thereafter.

Quercetin inhibited the niacin effect by 100%.

1. An anti-inflammatory composition, said composition comprising aflavonoid compound of basic structure 2-phenyl-4H-1-benzopyran or2-phenyl-4-keto-1-benzyopyran, a non-bovine sulfated proteoglycan and anolive kernel extract, and, optionally, one or more of a bitter willowextract and a serotonin inhibitor, wherein said composition has theproperty of protecting humans against superficial vasodilator flushsyndrome (“SVFS”).
 2. The composition of claim 1, wherein said flush isa carcinoid-associated flush, niacin-induced flush, mesentericfraction-induced flush, serotonin-induced flush, post-menopausal-inducedflush, alcohol-induced flush and monosodium glutamate-induced flush. 3.The composition of claim 1, wherein said flavonoid compound is selectedfrom the group consisting of quercetin, luteolin, myricetin andgenisatein, and a glycoside derivative of said flavonoids.
 4. Thecomposition of claim 1, wherein said proteoglycan is chondroitinsulfate.
 5. The composition of claim 1, wherein said serotonin inhibitoris a serotonin receptor antagonist.
 6. The composition of claim 5,wherein said antagonist is prochlorperazine or ketanserin.
 7. Thecomposition of claim 1, wherein said serotonin inhibitor is a mixedhistamine-1 and serotonin receptor antagonist selected from the groupconsisting of cyproheptadine or azatadine.
 8. The composition of claim 1consisting of 150-350 mg quercetin or luteolin, 50-150 mg chondroitinsulfate, 150-750 mg olive kernel extract, 5% by weight bitter willowextract, and, optionally, one or more of 1-4 mg cyproheptadine,prochlorperazine and azatadine.
 9. A method of protecting a humanagainst SVFS, comprising the steps of administering an effective dosefor an effective period of time a composition of claims 1, 3, 4, 5, 6, 7or
 8. 10. The method of claim 9, wherein said SVFS is caused bycarcinoid-associated flush, niacin-induced flush, serotonin-inducedflush, alcohol-induced flush mesenteric fraction-induced flush,post-menopause flush or monosodium glutamate-induced flush.